Tamoxifen is a cornerstone of adjuvant therapy for hormone-receptor- positive breast cancer. Tamoxifen is metabolized to the active metabolite endoxifen through enzymatic activity of a P450 gene, cytochrome 2D6 (CYP2D6), which has numerous variant alleles. Among women who take tamoxifen, those homozygous for inactive alleles have lower levels of serum endoxifen than those with two functional alleles. Several studies have reported increased risk of breast cancer recurrence or death in women homozygous for CYP2D6 inactive alleles, but others have found no association between CYP2D6 function and outcome. Larger studies, including population-based studies, are needed. We propose to explore this question in the large health plan member populations of Kaiser Permanente Northwest (KPNW) and Kaiser Permanente Hawaii (KPH). We will conduct a population-based case-control study to evaluate the hypotheses that, after adjuvant tamoxifen treatment for breast cancer, women with CYP2D6 genotypes associated with poor metabolism of tamoxifen have an elevated risk of breast cancer recurrence compared to women with CYP2D6 genotypes associated with extensive metabolism of tamoxifen. We further hypothesize that women with CYP2D6 genotypes associated with intermediate metabolism of tamoxifen are at intermediate risk. Study subjects will be drawn from all women in the two health plans diagnosed with hormone-receptor positive breast cancer from 1986 to 2007 who received adjuvant tamoxifen treatment and for whom stored formalin-fixed paraffin-embedded (FFPE) tissue is available for laboratory analysis. Cases (600) will be women with breast cancer recurrence. Randomly selected controls (1,200), women whose breast cancers did not recur, will be matched 2:1 to cases on pathologic and demographic characteristics. The Oregon Health &Science University (OHSU) Molecular Genetics Laboratory will extract genomic DNA from stored formalin-fixed paraffin-embedded tissue blocks and will perform the molecular testing to accurately determine CYP2D6 variant status. We will analyze CYP2D6 functional status in relation to breast cancer recurrence, considering other factors that may alter the association, in particular tamoxifen dose and duration, as well as concomitant medications that alter the activity of the CYP2D6 enzyme. This collaboration brings together Kaiser Permanente's access to two large health plan member populations, clinical biorepositories, and sophisticated epidemiologic and bioinformatics capabilities with OHSU's extensive laboratory capabilities and expertise in molecular genetics to expand the spectrum of translational research. Our ultimate goal is to learn more about the genetic factors underlying breast cancer treatment response in order to make breast cancer treatment more targeted and more effective. PUBLIC HEALTH RELEVANCE: Women with estrogen-receptor positive breast cancer may benefit from treatment with tamoxifen. However, a significant proportion of women do not respond well to the drug. Research suggests that genetic factors may be the reason. We will assess whether women with CYP2D6 genetic variants respond differently to tamoxifen treatment for breast cancer in two large populations. Our project will examine tissue samples for 1,800 women who received tamoxifen therapy over 22+ years to determine whether women with CYP2D6 variations respond better, or more poorly, to tamoxifen. We willl use pharmacy records to learn which women took tamoxifen, as well as other medications that may interfere with tamoxifen. We will use the electronic medical records of two managed care organizations, Kaiser Permanente Northwest and Kaiser Permanente Hawaii. We will also make use of the laboratory capabilities of Oregon Health &Sciences University. Our goal is to understand the genetic factors that affect women's response to tamoxifen so that women can receive treatment for breast cancer that is more targeted and effective.